Hypocalcaemia and hypoparathyroidism

Hypoparathyroidism (HPTH) refers to underactivity or complete loss of the parathyroid glands. This most commonly arises following neck surgery, but congenital, auto-immune and genetic causes are also seen. The diagnosis is confirmed biochemically with hypocalcaemia, hyperphosphataemia and low parathyroid hormone levels.

Has the patient undergone previous neck surgery of any form?  

Any neck surgery can lead to hypoparathyroidism (HPTH), which is most commonly transient but can be permanent in up to 1% all neck surgeries.

This is most commonly seen following extensive surgery for thyroid cancer, or other head and neck malignancy, but can also complicate surgery for benign thyroid disease, hyperparathyroidism, laryngeal or oesophageal pathology.

Transient post-surgical HPTH usually recovers within 6-12 months, and can be predicted by PTH levels >18ng/l.

Surgery for hyperparathyroidism may also lead to the hungry bone syndrome. After chronic hypercalcaemia, the dramatic fall in PTH leads to marked skeletal calcium uptake and the patient may become hypocalcaemic requiring high dose calcium replacement for several days post operatively.

Has the patient undergone radiation therapy to their neck?

External beam radiotherapy to the neck may also rarely damage the parathryoid glands leading to permanent HPTH.

Does the patient have a family history of hypoparathyroidism?  

Congenital and autoimmune HPTH may be associated with a positive family history of HPTH, or other immune conditions.

Di George syndrome results from a defect in the TBX-1 gene, necessary for normal embryonic development of the parathyroid glands. This syndrome may also cause cleft lip and palate, impaired renal function, ocular and cardiac abnormalities.

Mutations in the calcium sensing receptor may lead to hypocalcaemia with suppressed PTH. PTH gene mutations may also be associated with more severe HPTH.

Other rare syndromes causing HPTH occur with TBCE mutnations. Albright's hereditary osteodystrophy and pseudohypoparathyroidism may also lead to a biochemical picture similar to HPTH.

Does the patient have a family history of other endocrine or auto-immune diseases?  

Congenital and autoimmune HPTH may be associated with a positive family history of HPTH, or other immune conditions.

Autoimmune polyglandular syndrome type 1 typically presents in childhood, with skin infections (mucocutaneous candidiasis) then HPTH in 80% patients, and Addison's disease usually by age 25. 5hus is caused by mutations in the AIRE gene and is autosomaly recessiveley inherited.

Autoimmune HPTH may also arise with type 1 diabetes mellitus, Addison's disease, or thyroid disease as part of autoimmune polyglandular syndrome type 2.

Does the patient have any skeletal abnormalities e.g. short stature and short metacarpals?  

Pseudohypoparathyroidism type 1a is autosomal dominant, and associated with short stature, round face, and short metacarpals similar to Albright's hereditary osteodystrophy. This condition is due to mutations in the GNAS gene leading to resistance to PTH, and low calcium and high phosphateare seen, though PTH levels will be elevated. These patients may also exhibit rewistnace to TSH, LH and FSH.

Types 1b, 1c and 2 present with similar biochemical pictures, though the PTH resistance appears to be local and skeletal features are not seen.

Does the patient have diabetes, hypothyroidism or other thyroid pathology?  

These conditions may be associated with pseudohypoparathyroidism, though auto-immune conditions may also be associated with auto-immnue HPTH.

Reidel's thyroiditis can also rarely lead to infiltrative destruction of the parathyroid glands and HPTH.

Does the patient have deafness or renal problems?

Renal dysplasia, deafness and HPTH occur in the autosomal dominantly ihherited Barakat syndrome due to a mutation in the GATA gene. Renal problems may also arise as part of di George syndrome.

Does the patient have HIV AIDS or metastatic disease?

Metastatic cancer can occassionally lead to HPTH, as can AIDS though the mechanism is unclear.

Is the patient undernourished, alcoholic, or have any other potential cause of hypomagnesaemia e.g. severe burns or malabsorption?

Any cause of hypomagnesaemia may lead to reduced secretion of PTH, as well as PTH resistance and hence the clinical picture of HPTH.

Hypomagnesaemia may also occur with renal tubular defects. Very rarely, hypomagnesaemia may occur due to HNF1 mutations which more commonly cause maturity onset diabetes of the young (MODY).

Is the patient presenting in the neonatal period?

Transient HPTH may occur in offspring of mothers with hyperparathyroidism, in premature or very low birth weight babies. Hypomagensaemia in diabetic mothers may also lead to transient neonatal HPTH.

Does the patient complain of fatigue, weakness, tingling, numbness or paraesthesia around the mouth, hands or feet?

Perioral paraesthesia and cramps are the commonest symptoms of hypocalcaemia of any cause.

Does the patient complain of muscle cramps or twitching?  

Muscle cramps and sometimes spontaneous contractions are common symptoms of hypocalcaemia of any cause.

Severe cramp or carpopedal spasm iindicates more severe hypocalcaemia.

Has the patient ever presented with confusion or seizures?

This usually occurs only in very severe untreated hypocalcaemia, and so usually precedes diagnosis of HPTH.

Has the patient experienced any collapses, palpitations or known bradyarrhythmias?

Cardiac conduction disturbance usually only occurs with severe hypocalcaemia.

Does the patient describe depression, tiredness, weakness, constipation or polyuria?

Although depression is more common with HPTH, any of these symptoms raise the possibility of iatrogenic hypercalcaemia.

Has the patient ever developed cataracts or kidney stones?

 These complications may occur with hyperphosphataemia or iatogenic hypercalciuria.